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New Directions With Capecitabine Combinations in Advanced Breast Cancer

New Directions With Capecitabine Combinations in Advanced Breast Cancer

ABSTRACT: Capecitabine (Xeloda) offers a unique mode of action. The drug is currently being combined with other active agents in the treatment of advanced breast cancer. The recent demonstration of improved disease-free and overall survival with the capecitabine/docetaxel (Taxotere) combination, for example, has encouraged investigation of additional capecitabine/taxane regimens and schedules. A unique aspect of the metabolic activation of capecitabine is the ability of several anticancer drugs to upregulate the critical activating enzyme thymidine phosphorylase. These preclinical findings have led to clinical trials of several active agents in combination with capecitabine demonstrating high response rates in early results. In combination studies, capecitabine has been associated with very manageable toxicity. The combination of docetaxel/epirubicin (Ellence)/capecitabine (TEX) has shown particular promise in advanced disease, and should be evaluated in earlier disease. TEX is currently in phase III trials of advanced disease. In preclinical studies, the combination of capecitabine with inhibitors of HER2/neu (or the epidermal growth factor pathway) appears to hold significant promise both in breast cancer treatment and in treatment of other tumors expressing these receptors. Continued evaluation of capecitabine combinations will help to define the roles of this valuable agent, the only oral fluoropyrimidine for treatment of breast cancer available in the United States. [ONCOLOGY 16(Suppl 12):23-28, 2002]

Until recently, the management
of breast cancer with chemotherapeutic agents has led to modest benefits.[1] Hence, there is an urgent need
to introduce new active agents into the management of this disease. The
demonstration of a superior tumor response rate, time to disease progression,
and overall survival with the combination of capecitabine (Xeloda) and docetaxel
(Taxotere) compared with single-agent docetaxel in anthracycline-pretreated
patients indicates the important role of capecitabine in the treatment of
advanced breast cancer.[2]

The use of this agent in combination therapy in breast cancer patients,
however, has only begun to be explored, as the agent has a unique mode of action
and can be combined safely with a variety of agents.[3] Potential for
improvement in the therapeutic index of treatment with capecitabine-containing
combinations is suggested by (1) activity of other treatments (eg, taxanes,
cyclophosphamide [Cytoxan, Neosar], irinotecan [Camptosar], and vinorelbine [Navelbine],
as well as radiation therapy) in increasing tumor levels of thymidine
phosphorylase, the activating enzyme for capecitabine; (2) early-phase studies
showing activity of combinations with a variety of different agents; and (3)
preclinical data indicating potential for synergistic effects with a number of
combinations.[4]

Combinations With Taxanes

In North America, cyclophosphamide/doxorubicin combinations at full
conventional dosages have been the basis of breast adjuvant treatment.[5-7]
Based upon the enhanced response rates of phase III trials in the neoadjuvant
setting (National Surgical Adjuvant Breast and Bowel Project trial B-27) and in
the adjuvant setting (the Aberdeen trial), cyclophosphamide/doxorubicin followed
by docetaxel may offer a new standard approach in the management of
early-disease patients.[8-10] As capecitabine/taxane combinations demonstrate a
higher response rate and better survival than docetaxel alone in metastatic
disease, the combination is being advanced into treatment of earlier disease.
The current US Oncology Adjuvant Trial (XEL242) addresses the question of
whether or not the use of capecitabine/docetaxel following classical
cyclophosphamide/doxorubicin (Adriamycin) (AC) offers any benefit over
single-agent docetaxel following AC. Additional similar studies are in
development.

Weekly Taxanes

Weekly taxanes may offer a therapeutic advantage over traditional
every-3-week schedules of administration and are being actively studied.[11]
Because of the ease of administration of taxanes on a weekly schedule and the
possibility of repetitively up-regulating thymidine phosphorylase, additional
studies are exploring the feasibility of weekly taxane treatment in combination
with capecitabine.

Preliminary findings using this approach in 19 anthracycline-pretreated
patients with metastatic breast cancer demonstrated activity with acceptable
toxicity in an ongoing phase I/II study.[12] The recommended dose was identified
as intermittent oral capecitabine at 900 mg/m² twice daily on a 14-day schedule
every 3 weeks plus weekly docetaxel at 30 mg/m². There was a low incidence of
severe myelosuppression, with only one grade 4 event (neutropenia) being
observed; the most common grade 3 toxicity was palmar-plantar erythrodysesthesia
(in 3 of 19 patients). Objective tumor response was observed in two patients,
with seven patients demonstrating stable disease.[12]

Meza et al have reported findings in a phase II study of paclitaxel at 175
mg/m² every 3 weeks, plus capecitabine at 825 mg/m² twice daily on days 1 to
14, as first- or second-line treatment of metastatic breast cancer.[13] The
patients had a median age of 52 years (range: 35-76 years) and a median Karnofsky
performance status of 90. Among 47 evaluable patients, 34 patients received
this therapy as first-line treatment, and 13 patients as second-line treatment.
Of these patients, 13% (five patients with first-line treatment, and one with
second-line treatment) achieved a complete response; 30% of patients achieved
a partial response; and 38% had stable disease. Because of the small number
of patients, there is some variation in the partial responses in patients receiving
first- or second-line treatment (Figure
1
). Overall, median time to disease progression was 44 weeks.[13]

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